It is known that the rate of dissolution of a particulate therapeutic agent can increase with increasing surface area, i.e., decreasing particle size. Consequently, methods of making finely divided therapeutic agents have been studied and efforts have been made to control the size and size range of therapeutic agent particles in pharmaceutical compositions. For example, dry milling techniques have been used to reduce particle size and hence influence therapeutic agent absorption. However, in conventional dry milling, as discussed by Lachman, et al.. The Theory and Practice of Industrial Pharmacy, Chapter 2, "Milling", p, 45, (1986), the limit of fineness is reached in the region of 100 microns (100,000 nm) when material cakes on the milling chamber. Lachman. et al. note that wet grinding is beneficial in further reducing particle size, but that flocculation restricts the lower particle size limit to approximately 10 microns (10,000 nm). However, there tends to be a bias in the pharmaceutical art against wet milling due to concerns associated with contamination. Commercial airier milling techniques have provided particles ranging in average particle size from as low as about 1 to 50 .mu.m (1,000-50,000 nm).
Other techniques for preparing pharmaceutical compositions include loading therapeutic agents into liposomes or polymers, e.g., during emulsion polymerization. However, such techniques have problems and limitations. For example, a lipid soluble therapeutic agent is often required in preparing suitable liposomes. Further, unacceptably large amounts of the liposome or polymer are often required to prepare unit therapeutic agent doses. Further still, techniques for preparing such pharmaceutical compositions tend to be complex. A principal technical difficulty encountered with emulsion polymerization is the removal of contaminants, such as unreacted monomer or initiator, which can be toxic, at the end of the manufacturing process.
U.S. Pat. No. 4,540,602 (Motoyama et al.) discloses a solid therapeutic agent pulverized in an aqueous solution of a water-soluble high molecular substance using a wet grinding machine. However, Motoyama et al. teach that as a result of such wet grinding, the therapeutic agent is formed into finely divided particles ranging from 0.5 .mu.m (500 nm) or less to 5 .mu.m (5,000 nm) in diameter.
EPO 275,796 describes the production of colloidally dispersible systems comprising a substance in the form of spherical particles smaller than 500 nm. However, the method involves a precipitation effected by mixing a solution of the substance and a miscible nonsolvent for the substance and results in the formation of noncrystalline nanoparticles. Furthermore, precipitation techniques for preparing particles tend to provide particles contaminated with solvents. Such solvents are often toxic and can be very difficult, if not impossible, to adequately remove to pharmaceutically acceptable levels to be practical.
U.S. Pat. No. 4,107,288 describes particles in the size range from 10 to 1,000 nm containing a biologically or pharmacodynamically active material. However, the particles comprise a crosslinked matrix of macromolecules having the active material supported on or incorporated into the matrix.
U.S. Pat. No. 4,725,442 (Haynes) describes water insoluble therapeutic agent materials solubilized in an organic liquid and incorporated in microencapsules of phospholipids. However, the toxic effects of solubilizing organic liquids is difficult to overcome. Other methods of formation of pharmaceutical therapeutic agent microencapsule include:
a) Micronizing a slightlysoluble therapeutic agent by subjecting a mixture of the therapeutic agent and a sugar or sugar alcohol to highspeed stirring comminution or impact comminution (EP 411,629A) together with suitable excipients or diluents. Such a method of encapsule formation does not lead to particle size as small as obtained by milling.
b) Polymerization of a monomer in the presence of the active therapeutic agent material and a surfactant can lead to smallparticle microencapsule (International Journal of Pharmaceutics, Vol. 52, pp. 101 108, 1989). This process, however, contains difficulttoremove contaminants such as toxic monomers. Complete removal of such monomers can be expensive in manufacturing scales.
c) Codispersion of a therapeutic agent or a pharmaceutical agent in water with droplets of carbohydrate polymer has been disclosed (U.S. Pat. No. 4,713,249 and WO-84/00294). The major disadvantage of the procedure is that in many cases, a solubilizing organic cosolvent is needed for the encapsulation procedure. Removal of traces of such harmful cosolvents can lead to expensive manufacturing processes.
It would be desirable to provide stable dispersible therapeutic agent particles in the submicron size range which can be readily prepared and which do not appreciably flocculate or agglomerate due to interparticle attractive forces and do not require the presence of a crosslinked matrix. Moreover, it would be highly desirable to provide pharmaceutical compositions having enhanced bioavailability.